While heterogenous in presentation and treatment, gastrointestinal (GI) and hepatobiliary cancers have a commonality regarding their impact related to nutritional status, eating, bowel function, and depression, which can all negatively impact a patient’s health-related quality of life (HRQOL). The purpose of this chapter is to provide an overview of HRQOL and psychosocial implications in common GI and hepatobiliary cancers, including cancer of the esophagus, stomach, colon, rectum, pancreas, and liver.